19-substituted-5alpha-halogen-6beta:19-oxido-pregnanes



United States Patent 3,174,969 19-SUBSTITUTED-5oz-HALOGEN-6B:19-

' OXIDO-PREGNANES Albert Wettstein, Riehen, Georg Anner, Karl Heusler, and Jaroslav Kalvoda, Basel, Hellmut Ueberwasser, Rieheu, and Jules Heer, Binningen, Switzerland, assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 7, 1962, Ser. No. 222,204

Claims priority, application Switzerland, July 15, 1960, 8,133/60; Oct. 28, 1960, 12,107/60; Dec. 23, 1960, 14,393/61; Apr. 5, 1961, 3,989/61; June 2, 1961, 6,479/61; June 13, 1961, 6,895/61; Sept. 18, 1961, 10,803/61; Jan. 9, 1962, 185/62 6 Claims. (Cl. 260-23955) This application is a continuation in-part of our copending application Ser. No. 122,657, filed July 10, 1961, now abandoned, by Albert Wettstein et al.

- The present invention relates to novel 3: 19-dioxygenated a-halogen-6/3:19-oxido-pregnanes, more especially to compounds of the formula Hal wherein R and R stands for oxo or hydrogen together with hydroxy or acyloxy, R stands for hydrogen, 0x0 or hydrogen together with hydroxy or acyloxy, R stands for hydrogen, hydroxy or acyloxy, R stands for oxo or hydrogen together with hydroxy or acyloxy and Hal stands for a halogen with a molecular weight above 30, especially for chlorine and bromine.

The acyloxy radicals mentioned above, representing esterified hydroxyl groups, are more especially those of aliphatic, cycloaliphatic, cycloa'liphatic-aliphatic, arali phatic, aromatic or heterocyclic carboxylic acids containing at most canbon atoms, such as for example formic, acetic, propionic, butyric, Valerie, trimethylacetic, caproic, oenantic, decanoic, trifluoroacetic, canbonic-monomet-hylester or carbonic-monoethylester hexahydrobenzoic, cyclopentylpropionic, phenylpropionic, benzoic or furoic acid.

The compounds of the present invention are extremely useful intermediates for the production of 19-nor-pregnanes to which class of compounds belong several well known progcstational agents such as 19-nor-progesterone, 17a hydroxy-l9-nor-progesterone and especially its esters, 6-dehydro-l9-nor-progesterone etc.

The l9-no-r-pregnenes are-produced from the 3: 19-dioxygenated 5a-halogen-6/3: l9-oxidopregnanes of the present invention by treating them with zinc and acetic acid at elevated temperature whereby A -19-oxo-pregnenes or A pregnene-19-acids are formed. After converting the 3- substituent into a 3-oxo-group (e.g., by hydrolysis of a 3- acyloxy group and oxidation of a 3-hydroxy group formed) 19-oxygenated A -3-ketones are obtained from which the angular C-19-substituent is eliminated in known manner.

Among the 19-oxygenate-d 5a-halogen-6fl: l9-oxidopregnanes of the present invention the following are particularly important: 3,8:11a:19-tril1ydroxy-5a-chloro-6p: 19-oxido-20-oxo-pregnane, 3 ,8: 11a: 19 20-tetrahydrox 5a-chloroor Su-bromo-SB: l9-oxido-pregnane, the 19:6,8- lactones of 3 8: 6/3: 110: 20 3-tetrahydroxy-5 a-chloro-pregnane-19-oic acid, of 3B:6,8:ZOB-trihydroxy-Sa-chloro-l1- oxo-pregnane-l9-oic acid, of 35:6;1:llfl:20,8-tetrahyroxy- Sa-chlOrO-pregnane-l9-oic acid, of 3,816,6: 17a-trihydroxy- 5a-chloroor -5owbromo-20-oxo-pregnane-l9-oic acid and the corresponding compounds in which some or all of the free hydroxyl groups are acylated.

The above lactones are obtained from the corresponding 19-unsubstituted 613:19-oxido-pregnanes by oxidation with chromium trioxide in acetic acid at a temperature of 60 to The 19-unsubstituted 6,8:19-oxido-pregnanes are obtained either by treating a 5a-halogen-6/i-hydroxypregnane with lead tetraacetate in boiling benzene or cycl'ohexane for several hours or by reacting a Six-halogen- 6B-hydroxy-pregnane in boiling cyclohexane solution wit-h monovalent, positive iodine preferable in the presence of free iodine and strong visible light for 10 to minutes. The monovalent positive iodine may be obtained from N- iodo-succinimide or from silver acetate and iodine or mercuric acetate and iodine. An especially efiicient method for the preparation of the 5ot-halogen-6fl: 19- oxido-pregnanes consists in treating a 5a-halogen-6B-hydroxy-pregnane in an apolar solvent, e. g., in boiling cyclohexane solution with lead tetraacctate and iodine. If 1 l-oxygenated (especially 1 lot-acyloxy) -5a-halo-gen-6flhydroxy-pregnanes are treated with lead tetraacetate and iodine under the above defined conditions, Soc-halogen- 6B:19-oxido-19-hydroxy-pregnanes are formed directly during the reaction. These may be oxidized to 19:6 8- lactones with chromium trioxide in acetone-sulfuric acid at last temperature.

The following examples illustrate the invention. temperatures are given in centigrade.

Example 1 The (a) A suspension of 10 grams of calcium carbonate and 30 grams of lead tetraacctate in 1 liter of cyclohexane is heated to 80 C., treated with 8.0 grams of iodine and then with 5 grams of 36:20 B-diacetoxy-5a-chlorofl-hydroxy-Sa-pregnane and the reaction mixture is refiuxed for 3 hours and then cooled and filtered. The residue is washed with ether, the filtrate extracted with sodium thiosulfate solution of 10% strength, dried and evaporated under reduced pressure, to yield 6.1 grams of a solid crude product which on crystallization from acetone-i-hexane yields pure 3,8:205 diacetoxy 5a chloro-6B:19-oxido-5a-pregnane melting at 148 to 150 C. Optional rotation [a] =+25 (in chloroform).

A solution of 4.0 grams of this compound in methanol is treated with 4.0 grams of potassium carbonate and water and refluxed for one hour, then evaporated in a water-jet vacuum and from the residue the crude 3,8:205 dihydroxy 50c chloro 65:19 oxido 5oz pregnane melting .at 237 to 240 C. is isolated in the usual manner.

A mixture of 1.0 gram of the above compound, 50 cc. of pyridine and 2.2 grams of chromium trioxide is stirred for 20 hours at 60 C. and the reaction mixture is then worked up as usual. Recrystallization of the crystalline residue yields pure a -3z20-dioxo-6flz19-oxidopregnene (6fi:19-oxido-progesterone) melting at 142- 143 C. Optical rotation [a] =--18.8 (in chloroform).

(b) 1.0 gram of the 3,8:20fi diacetoxy 5a chloro- 6,8:19-oxido-5a-pregnane described in part (a) is oxidized in 30 cc. of glacial acetic acid with addition of a solution of 1.5 grams of chromium trioxide in 1.5 cc. of water for 20 minutes at 70 C. By working up in the usual manner there is obtained a crude product which on recrystallization from methylene chloride-l-ether yields the pure 19:6,8 lactone of 3520;? diacetoxy 51x chloro 6,8-hydroxy-5a-pregnane-l9-acid melting at 189 to 190 C.

In an analogous manner there is obtained from the 18:20 lactone of 3B acetoxy 50c chloro 6,8219 oxido-20fi-hydroxy-5u-pregnane-18-acid described in Example 13 or" our copending application Ser. No. 222,168,

filed September 7, 1962, in addition to acid reaction products, the 18:20; 19:65 dilactone of 3B acetoxy- 5a chloro 65:2013 dihydroxy 5a pregnane 18: 19 diacid.

Example 2 (a) A suspension of 110 grams of lead tetraacetate and 50 grams of dry calcium carbonate in 4.5 liters of cyclohexane is stirred for about 40 minutes at the boil. 25 grams of 3B acetoxy 50c chloro 6,8 hydroxy 20-oxo-pregnane and 32 grams of iodine are then added and the solution is kept at the boil while being irradiated with a 1000 watt lamp and stirred until the color of iodine has completely disappeared (about 30 to 90 minutes). The whole is then cooled, the undissolved salts are filtered oil? and the filter residue is rinsed with cyclohexane. The filtrate is washed with dilute sodium thiosulfate solution and with water, dried and evaporated in a water-jet vacuum. Crystallization of the crude product from ether yields 19.2 grams of pure 3 fi-acetoxy- 5a chloro 6,8: 19 oxido 20 oxo pregnane melting at 150 to 153 C. From the mother liquor another 3.3 grams of a slightly less pure substance can be isolated. Optical rotation of the pure compound [oc] :|65 (in chloroform). Its infra-red spectrum contains bands, inter alia, at 5.78, 5.88, 6.70, 8.13, 9.12, 9.66, 10.60, 10.86 and 11.75;.

In an analogous manner there are obtained From 3:170: diacetoxy 50c chloro 6,8 hydroxy 20 oxo pregnane the 35:17 diocetoxy 50a chloro 613219 oxido 20 oxo pregnane melting at 187 to 187.5 C.,

From 3,8 acetoxy 5a chloro 6p hydroxy 17cc valerianyloxy 20 oxo pregnane the 35 acetoxy 5oz chloro 65:19 oxido 17cc valerianyloxy 20 oxo-pregnane, and

From 33 acetoxy 5a chloro 6,8 hydroxy 17a methoxy 20 x0 pregnane the 3B acetoxy a I chloro 65:19 oxido 17a methoxy oxo pregnane.

V The chlorohydrin used as starting material is prepared in the following manner: A solution of 150 grams of pregnenolone acetate in 5 liters of ether is treated with 150 grams of chlorinated lime (containing 30% of active chlorine) and 8.2 liters of water and the reaction mixture is vigorously stirred. After 5 minutes 105 cc. of glacialacetic acid and after another minutes 500 cc. of potassium iodide solution of 10% strength are added. Finally, the aqueous phase is separated, and the ethereal solution is washed with sodium thiosulfate solution of 10% strength, dilute sodium bicarbonate solution and with water, dried and evaporated in a water-jet vacuum. The residue is treated with 800 cc. of acetone and kept overnight at 0 C., to yield 47.5 grams, and from the mother liquor another 58-grams, of 3p-acetoxy-5a-chloro- 6B-hydroxy-20-oxo-pregnane which melts at 196 to 197 C. after recrystallization from acetone. Optical rotation [u] =|-25.5 (in chloroform). The infra-red, spectrum of the compound displays bands, inter alia, at 2.75, 5.78, 5.88, 8.12, 8.68, 9.68 and 9.72

In an analogous manner addition of hypochlorous acid on to the 17oc-acetoxy-pregnenolone acetate yields 3,8: l7ocdiacetoxy 5a chloro 6B hydroxy 20 oxo pregnane.

(b) 10.0; grams of 3,6 acetoxy 50c chloro 65:19 oxido-20-oxo-pregnane in 180 cc. of acetic anhydride are treated with 4.0 grams of para-toluenesulfonic acid and heated in a bath maintained at 140 to 150 C. for 4 hours under a pressure of 50 to 60 mm. Hg, during which 90 cc. of solvent are distilled off. The reaction mixture is cooled, poured over ice and water and extracted with a 3:1-mixture of ether and methylene chloride. The extracts are Washed with sodium bicarbonate solution and with water, dried and evaporated. The residue (10.40 grams) is dissolved in benzene and the solution is filtered through grams of alumina. The eluates yield 10.1 grams of crude product which still contains about 15% of starting material. Crystallization from methylene chloride-l-ether-kpetroleum ether yields pure Almo) 3/3:20 diacetoxy 5a chloro 613219 oxido-pregnene melting at 171 to 172 C. Optical rota= tion [a] =+18.4 (in chloroform). The infra-red spec}- trum of the compound contains bands, inter alia, at 5.76, 6.70, 7.30, 8.16, 9.13, 10.60 and 10.87 a.

A solution of 10.1 grams of crude A -3fi:20'-diace- (OXY-SOt-ChlOI'O-Gfifi 19-oxido-pregnene in 250 cc. of benzene is treated with 240 cc. of an ethereal solution of perbenzoic acid (containing 2 molecular equivalents of per-acid calculated on the enol acetate) and kept for 5 hours at room temperature, after which time 70.2% of the amount of per-acid calculated for complete oxidation has been consumed. The reaction mixture is diluted with ice water, extracted with ether and the extracts are washed with water, sodium bicarbonate solution and water. The dried ethereal solution yields 9.90 grams. of crude epoxide. After recrystallization from methylene chloride-l-ether pure 35:20-diacetoxy-5a-chloro-6fi: l9gl7az20-bisoxidopregnane melts at 192 to 194 C. Optical rotation [a] =+14.4 (in chloroform). The infra-red spectrum of the compound contains bands, inter alia, at 5.76, 6.70, 7.30, 8.13, 8.58, 9.67, 10.6 6 and 10.81

A mixture of 10.0 grams of crude 3,8:20-diacetoxy-5achloro-6B:19;17u:20-bisoxido-pregnane, 800 cc. of alcohol and 45 cc. of aqueous sodium hydroxide solution of 2.4% strength is kept for one hour at room temperature, treated with 500 cc. of water and concentrated in a water-jet vacuum to half the volume. The concentrate is heated for 3 hours at 60 C., and the precipitate is filtered oif, thoroughly washed with water and the filter residue is dried, to yield 9.85 grams of crude product which after crystallization from methylene chloride-, methanol yields 3.90 grams of pure 3B:17tx-dihydroxy-5a-chloro-Gfi:19-oxido-20-oxo-- pregnane melting at 251 to 253. Optical rotation [a] =+22.4 (in chloroform-l-alcohol). From the mother liquor another compound separates out which melts at 251 to 253 C.; it is probably a rearrangement product of the above diol.

A mixture of 200 mg. of 313:17a-dihydroxy-5a-ehloro 6B:19-oxido-20-oxo-pregnane, 1.0 cc. of acetic anhydride and 1.0 cc. of pyridine is stirred for 14 hours, with the starting material slowly passing into solution. The solu tion is then poured into ice water and extracted with a mixture of ether and methylene chloride. The extracts are washed with water, hydrochloric acid, sodium bicarbonate solution and with water and dried, to yield 210 mg. of crude product which is crystallized from ether-lpetroleum ether to yield 185 mg. of pure 3,8-acetoxy- I 5oz chloro 66:19 oxido 17a hydroxy 20 oxopregnane melting at 166 to 167 C. Occasionally, the compound is obtained in a crystalline modification melting up to about C. Optical rotation [a] =2.1 (in chloroform). Its infra-red spectrum contains bands, inter alia, at 2.74, 2.82, 5.76, 5.85, 6.69, 7.30, 8.10, 9.65 and 1086 A mixture of 100 mg. of 3,8:l7a-dihydroxy-5a-chloro- 6B:19-oxido-20-oxo-pregnane, 1.0 cc. of acetic anhydride and 100 mg. of para-toluene sulfonic acid is stirred for 2%. hours at 40 C., then poured into a mixture oil-'50 cc. of ice water and 0.5 cc. of pyridine, diluted w' hether after 10 minutes, and the extracts are washed 1th sodium bicarbonate solution and with water. Recrystallization of the evaporation residue (106 mg.) from ether+petroleurn ether yields 98 mg. of pure 3,8:17a-diacet'oxy-5achloro-6,8:19-oxido-20-oxo-pregnane melting at 187 to 187.5 C. Optical rotation [a] =6.2 (in chloroform). The infra-red spectrum of the compound contains bands, inter alia, at 5.77, 6.68, 7.79, 8.10, 9.65, 10.39 and 10.85

r Example 3 2.5 grams of 3B317oc-diElCEtOXY-Sa-ChlOIO-6/3Z19-0Xld0- 20-oxo-pregnane are dissolved in 50 cc. of glacial acetic acid. The solution is heated to 70 C., and a solution of 3.75 grams of chromium trioxide, in 3.75 cc. of water and 30 cc. of glacial acetic acid is added in the course of about 4 minutes, and the whole is stirred for 30 minutes at 70 C. The reaction mixture is cooled, poured on to water and the precipitated white crystals filtered off with suction. There are obtained 2.48 grams of the crude 19:6,B-lactone of 3B:17a-diacetoxy-5a-chloro- 6fi-hydroxy-20-oxo-pregnane-19-acid melting at 215-219 C. The pure compound recrystallized from a mixture of methylene chloride and ether melts at 235237 C. Infra-red bands inter alia at 5.64 1 ('7 lactone); 5.80 1. (acetate-l-ZO ketone); 8.08 9.05 1; 9.1'6/.L; 9.25 t; 9.60 4; 1034 1; 1078 1 and 12.07 t.

1.7 grams of the 19:6 9-lactone of 3fizl7a-diacetoxy-5uchloro-6fl-hydroxy-20-oxo-pregnane-19-acid are stirred in 104 cc. of methanol for 45 minutes in a bath heated to 70 C. after adding 340 mg. of sodium bicarbonate and 3.1 cc. of Water. The reaction mixture is cooled, 500 cc. of water are added and extraction is carried out with ether. The extracts are washed with water and dried to yield 1.57 grams of crude 1916fi-lactone of 3 8: 6fi-dihydroxy 5a chloro-17a-acetoxy-20-oxo-pregnane-19-acid which after being recrystallized from a mixture of methylene chloride and ether, melts at 246248 C.

Example 4 A suspension of 17.5 grams of lead tetraacetate and 8.0 grams of calcium carbonate in 800 cc. of cyclohexane is first heated for 30 minutes to boiling point while stirring. 4.0 grams of 3 3:11a:20/8-triacetoxy-5u-chloro-6/3-hydroxypregnane and 5.13 grams of iodine are then added and the mixture is heated for another hour to boiling point while being stirred and exposed to a 500 watt lamp, the color of the iodine slowly disappearing. After the reaction time has expired, the mixture is cooled, the insoluble salts are separated by filtration and the filtrate is washed with sodium thiosulfate solution and with Water. The aqueous solutions are extracted once more with ether and the combined organic solutions are dried and evaporated in a water-jet vacuum. The partly crystallizing crude product obtained (6.146 grams) is dissolved in 100 cc. of glacial acetic acid to reduce the starting material contained therein and the solt'uion is stirred for 2 hours at 80 C. after adding 10 grams of zinc dust. The undissolved zinc is then filtered off and the filtrate is diluted with methylene chloride and Washed with sodium bicarbonate solution and with water. 4.253 grams of crude product are obtained from the dried organic solutions after evaporation. By crystallization from ether, 923 mg. of 3 ,8: 11a:20/3-triacetoxy-5e-chlorO-QB: 19-oxidopregnane having a melting point of 22'8230 C. can be separated therefrom (conversion from 185 C.); [a] =6.2 (in chloroform); IR bands inter alia at 5.77 1 and 8.09 1. (acetates), 9.63 t; 9.75/L and 10.84

The mother liquor is evaporated to dryness and chromatographed on 100 grams of aluminum oxide. With 900 cc. of hexane, 900 cc. of hexane-benzene mixture (4: 1) only 81 mg. of oily by-products are eluted. From the fractions eluted with another 300 cc. of benzenehexane mixture (2:1) there are obtained by crystallization from aqueous methanol 119 mg. of A -3fi:11a:20[ triacetoxypregnene, which has been produced by zinc reduction of the 5a-chloro-6B-hydroxy compound. The following 300 cc. of benzene-hexane mixture (2:1) and 300 cc. of benzene contain mixtures of substances, While the evaporation residues of the fractions eluted with 900 cc. of benzene and 600 cc. of benzene-ethyl acetate mixture (9:1), when crystallized from ether, yield a further 411 mg. of the above-described 3B:llazZOfi-triacetoxy-Sachloro-6fi:19-oxido-pregnane. Finally from the fractions eluted with benzene-ethyl acetate mixture (1:1), with ethyl acetate and with methanol, 718 mg. of 3 3211ot220/3- triacetoxy 5a chloro-6 3:19-oxido-19-hydroxypregnane having a melting point of 232233 C. are obtained by crystallization from methylene chloride-ether;

(in chloroform-alcohol in a ratio 1:1). IR bands inter alia at 2.79 and 2.93 (OH), 5.78/1. and 8.12 (acetates); 9.30 5 9.70/.L, 10.5511. and 10.91 i.

The 35: ::20/3 triacetoxy 5 0c chloro-6fi-hydroxypregnane employed as starting material is prepared as follows: 18.71 grams of A -3-oxo-1la-acetoxy-ZOfl-hydroxypregnene are heated to boiling point in 100 cc. of isopropenyl acetate after adding 0.1 cc. of concentrated sulfuric acid. After one hour, 10 cc. of solvent are distilled off, boiling is then continued for another hour under reflux and the solution is then evaporated in a water-jet vacuum after adding 500 mg. of anhydrous sodium acetate. The residue is taken up in methylene chloride and the solution is washed with water, dried and once more evaporated. From the crude product (21 grams), 13.66 grams of pure A -3:11a:20/3-triacetoxy-pregnatriene having a melting point of 150 C. are obtained by crystallization from ether; [0c] =-l44.3 (in chloroform); UV maximum at 235 m t (e=l9,500); IR bands inter alia at 5.77 t (with shoulder at 5.68 i) and 8.16 1. (acetates), 9.76 t; 1040 1. and 10.83 t.

12.0 grams of this enol acetate are dissolved in 900 cc. of alcohol. A solution of 6.0 grams of sodium borohydride in 120 cc. of 70% aqueous alcohol is added to the solution, which has been cooled to +5 C., and the reaction mixture is allowed to stand for 3 days at 0 C. 10 cc. of glacial acetic acid are then dropped in while stirring and the reaction mixture is concentrated in a water-jet vacuum to about 100 cc., diluted with methylene chloride and Washed with water. 11.52 grams of a residue are obtained from the dried methylene chlor de solution after evaporation and from this 9.78 grams of pure A -3B-hydroxy-11e:20 6-diacetoxypregnene can be isolated by crystallization from ether. The compound, after being dissolved once more in methanol and allowed to crystallize, melts at 162-165" C. [oc] =69.6 (in chloroform); IR bands inter alia at 2.74 1 (OH), 5.78 t and 8.09 (acetates); 9.76/1. and 10.45 t.

9.78 grams of this compound are allowed to stand overnight at room temperature in 50 cc. of pyridine and 30 cc. of acetic anhydride. The reaction mixture is then evaporated to dryness in a water-jet vacuum and the residue is crystallized from aqueous methanol. 10.1 grams of A 3,8:1ImZO/E-triacetoxypregnene having a melting point of 141143 C. are obtained; [a] =59.4 (in chloroform). IR bands inter alia at 5.78 and 8.09 1 (acetates), 9.76 14 10.44 1 and 10.93

3.0 grams of A 35:1lotz20/3-triacetoxypregnene are dissolved in 180 cc. of ether. After adding 180 cc. of water and 3.0 grams of chlorinated lime, the reaction solution is thoroughly stirred and 2.1 cc. of glacial acetic acid are then added. The two phases are then well mixed for 40 minutes with vibromixer, 50 cc. of 2% sodium thiosulfate solution and 50 cc. of 5% potassium iodide solution are then added, separation is carried out and the organic solution is washed several times with water. 1.78 grams of 3fltlla120fi triacetoxy-5a-chloro-6fi-hydroxypregnane having a melting point of 225227 C. are obtained from the evaporation residue (3.417 grams) by crystallization from ether; [u] =--43.2 (in chloroform); IR bands inter alia at 2.74 t (OH); 5.78 t and 8.09 1 (acetates); 9.30 4; 9.56 1; 9.75 4 and 10.45 4.

Example 5 A solution, cooled to 0 C., of 100 mg. of 3/32l1oc120fltriacetoxy 5a-chloro-6,8:19-oxido-19-hydroxypregnane in 10 cc. of acetone is stirred for 10 minutes at 0 C. after adding 0.2 cc. of a 26.6% solution of chromium trioxide in sulfuric acid of 42% strength. 500 mg. of crystalline 3 8 sodium acetate are then added and the solution is diluted R stands for a member selected from the group consist- With methylene chloride and Washed several times With ing of oxo, hydrogen, hydrogen together With hywater. 95 mg. of crystallized lactone of 352110;:205- droxy and hydrogen together with acyloxy, triacetoxy a chloro-6fi-hydroxypregnane-19-acid, hav- R stands for a member selected from the group coning a melting point of 246247 C., are obtained from the 5 sisting of hydrogen, hydroxy and acyloxy, dried methylene chloride solution; [a] =50.1 (in R stands for a member selected from the group conchloroform); IR bands inter alia at 5.58;; (lactone), sisting of oxo, hydrogen together with hydroxy and 5.75 and 8.09 (acetates); 9.26 9.65 and 10.77,u. hydrogen together with acyloxy, and

What is claimed is: Hal stands for a halogen atom selected from the group 1. 3:19-oxygenated 5oc-halogen-6fi:l9-oxido-pregnanes 10 consisting of chlorine and bromine, said acyloxy of the formula groups being derived from carboxylic acids having CH3 up to carbon atoms. cll"R 2. The 1926fl-lact0ne of 3B:205-diacetoxy-5 x-chloro- 5 6-fl-hydroxy-pregnane-l9-oic acid. 15 3. The 19:6B-lactone of Sfi:17a-diacetoxy-5ot-chlorofl-hydroxy-ZO-oxo-pregnane-l9-oic acid. x 4. The 19:6fi-lactone of 3 6:6fi-dihydroxy-5a-chloro- Q 17a-acetoxy-ZO-oxo-pregnane-19-oic acid.

5. 3flzlloaz20fi-triacetoxy 5a chloro-6B:19-oxido-19 R1 20 hydroxy-pregnane. fi 6. The 19:65- lactone of 35: llaZZOfl tnacetOXy-Sachloro-6B-hydroXy-pregnane-l9-oic acid. wherein R stands for a member selected from the group con- References Cited in the file of this patent sisting of hydroxy and acyloxy,

R stands for a member selected from the group con- 6 UNITED STATES PATENTS sisting of oxo and hydrogen together with hydroxy, 3,033,362 R gold et al May 8, 1962 

1. 3:19-OXYGENATED 5A-HALOGEN-6B:19-OXIDO-PREGNANED OF THE FORMULA 